title: Rapamycin attenuates the expression of cocaine-induced place preference and behavioral sensitization.
abstract: The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that controls global protein synthesis, in part, by modulating translation initiation, a rate-limiting step for many mRNAs. Previous studies implicate mTOR in regulating stimulant-induced sensitization and antidepressive-like behavior in rodents, as well as drug craving in abstinent heroin addicts. To determine if signaling downstream of mTOR is affected by repeated cocaine administration in reward-associated brain regions, and if inhibition of mTOR alters cocaine-induced behavioral plasticity, C57BL/6J mice received four intraperitoneal (i.p.) injections of 15 mg/kg cocaine and levels of phosphorylated P70S6 kinase and ribosomal S6 protein-two translational regulators directly downstream of mTOR-were analyzed by immunoblotting across several brain regions. Cocaine place preference and locomotor sensitization were elicited by four pairings of cocaine with a distinct environment and the effects of mTOR inhibition were assessed by pre-treating the mice with 10 mg/kg rapamycin, 1 hour prior to: (1) each saline/cocaine conditioning session; (2) a post-conditioning test; or (3) a test for locomotor sensitization conducted at 3 weeks withdrawal. While systemic pre-treatment with 10 mg/kg rapamycin during conditioning failed to alter the development of a cocaine place preference or locomotor sensitization, pre-treatment prior to the post-conditioning test attenuated the expression of the place preference. Additionally, rapamycin pre-treatment prior to a cocaine challenge 3 weeks post-conditioning blocked the expression of the sensitized locomotor response. These findings suggest a role for mTOR activity, and perhaps translational control, in the expression of cocaine-induced place preference and locomotor sensitization.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of California-Santa Barbara, CA 93106, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Bailey
authors.forename: Dzwokai
authors.initials: D
authors.lastname: Ma
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D003042:Cocaine / Q000037:antagonists & inhibitors*; D003216:Conditioning, Operant / Q000187:drug effects; D004347:Drug Interactions; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D012054:Reinforcement, Psychology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D003042:Cocaine; D020123:Sirolimus